Amyotrophic lateral sclerosis (ALS, motor neuron or Lou Gehrig's disease) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative disorders that are associated with the neural aggregation of specific proteins. Recently, the DNA/RNA-binding proteins FUS (Fused in Sarcoma) and TDP-43 (TAR DNA-binding protein) were implicated in these diseases. Just as mutations in superoxide dismutase-1 (SOD1) were previously linked to some familial forms of ALS, mutations in the genes that code FUS and TDP-43 have likewise been linked to familial ALS. However and perhaps more importantly, wild-type FUS and TDP-43 have also been identified as key components of the neuronal ubiquitinated cytosolic inclusions in cases of sporadic ALS, which accounts for 85-90% of all ALS cases. The finding that these two proteins are so intimately linked to ALS and FTLD neurodegeneration shifts the paradigm in our understanding of the mechanisms that underlie these diseases. And yet, exactly how protein aggregation leads to neuronal cell death is unknown, hampering the development of effective treatment strategies. We recently developed a yeast model for studying FUS aggregation and toxicity that recapitulates observations made in diseased neurons. The over-expression and concomitant aggregation of FUS is cytotoxic and causes severe inhibition of cell growth, offering a mechanism for performing high-throughput screens of genetic and chemical modifiers of toxicity. We plan to use the chemical library screening offered through the Molecular Libraries Probe Production Centers Network (MLPCN) to identify small molecules that can ameliorate FUS-induced toxicity. Promising candidates will be confirmed in laboratory-scale experiments and will be further validated in an animal FUS-toxicity model. Additionally, drug candidates will be cross-tested in other established neurodegenerative disease-related yeast models. Our system offers a fast and inexpensive screening mechanism to find drug leads that may eventually be developed into therapeutics capable of reducing the neurodegeneration in ALS, FTLD and other disorders.